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Background: Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after Hematopoietic Stem Cell Transplantation (HSCT). Previously, in large patient cohorts, we identified increased numbers of CD56 bright Perforin - regulatory-like NK cells (NK reg -like) associated with cGvHD suppression. Thus, we hypothesized that NK reg -like cells may be a potential candidate for cGvHD cell therapy., Aim: To expand NK reg -like cells while maintaining regulatory phenotype and function., Methods: Total NK cells were first expanded with IL-2, which was then combined with rapamycin, Transforming Growth Factor Beta 1 (TGF-β1), NECA (Adenosine A2A receptor (A2AR) agonist), metformin, or dexamethasone, to prevent change in cell phenotype/function. The functional characteristics were evaluated via T cell suppression assays and the phenotype was measured using flow cytometry. The optimal expansion protocol was compared in terms of function and metabolism for three NK expansion media, and cells from cord vs. peripheral blood. Further, expanded NK reg -like cell gene expression was characterized using bulk RNA sequencing. Finally, NK reg -like cells were differentiated from CD34 + hematopoietic stem and progenitor cells (HSPCs) and compared in terms of proliferation and function., Results: The expansion of total NK cells found the addition of TGF-β1 and/or NECA with the pulsing of rapamycin in IL-2 containing media to prevent NK reg -like differentiation (up to 200-fold expansion). Expanded NK reg -like cells maintained a phenotype, transcriptome, and T cell suppression similar to freshly isolated NK reg -like cells. NK reg -like expansion was greatest in the Immunocult media (up to 300-fold), and NK reg -like cells from peripheral blood demonstrated significantly greater proliferation than cells isolated from cord blood (65-fold). The metabolic profile of NK reg -like and cytolytic NK cells appeared similar at baseline, though rapamycin induced a shift to oxidative over glycolytic metabolism. Further, we demonstrated that suppressive NK reg -like cells may alternatively be expanded from CD34 + cells isolated from cord blood, reaching an average 340-fold expansion., Conclusions: In conclusion, our studies have optimized two alternative expansion approaches for deriving functional NK reg -like cells. Additionally, evaluating the transcriptomic and metabolic characteristics provides useful information regarding NK reg -like cell function and differentiation. With further optimization and in vivo validation, we may work towards preparing these cells as a therapy for cGvHD., Competing Interests: Declaration of competing interest None of the co-authors have any conflicts of interest to declare for the project., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Various essential thrombocythemia (ET)-related stroke mechanisms have been proposed, including microcirculatory disturbance due to coagulopathy, vasculitis, and embolism due to thrombus formation in large vessels. However, the stroke mechanism in ET remains largely unexplored. The purpose of this study was to evaluate magnetic resonance image (MRI) features of ischemic stroke in ET and determine the potential stroke mechanism., Methods: We retrospectively collected data from 21 acute ischemic stroke patients with ET who were admitted to two stroke centers between 2010 and 2023. ET was diagnosed according to the World Health Organization criteria. We evaluated MRI features including the diffusion-weighted image (DWI) lesion pattern, and the presence of hemorrhagic transformation and intracranial artery steno-occlusive lesion, as well as other etiological workup results., Results: Of 21 patients, 20 exhibited multiple ischemic lesions on DWI, mainly within a single vascular territory. Cortical infarcts were observed in 19 patients. Hemorrhagic transformation occurred in 15 patients. Additionally, 15 patients had intracranial steno-occlusive arteries, which regressed to normal in 11 patients during follow-up. Out of all patients, only 2 had potential causes of stroke other than ET (1 with atrial fibrillation and 1 with intracranial atherosclerotic stenosis). The remaining 19 patients had ET as the only identified potential cause., Conclusions: MRI features, including DWI lesion pattern in ischemic stroke patients with ET, suggested embolic etiology despite the absence of major embolic sources. Intra-arterial thrombus appears to be part of the stroke mechanism related to ET and may contribute to ischemic stroke in ET., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: This study aimed to explore the direct and indirect effects of social frailty on functional state trajectories mediated by subjective cognitive function in older adults., Design: Longitudinal study., Setting and Participants: Overall, 514 adults aged ≥65 years living in a suburban area of central Japan were included in this study., Methods: Five-item social frailty index (going out, visiting, feeling helpful, living alone, and talking to others), subjective cognitive function from the Kihon Checklist, and instrumental activities of daily living disability. Latent growth curve models were applied to examine the longitudinal relations among the variables., Results: During the 6-year follow-up in latent growth curve models, the initial level of social frailty in older adults was negatively associated with that of functional status (β = -0.53, P < .001), and the rate of change in social frailty was negatively associated with that in functional status (β = -0.78, P < .001). In the mediation model, the indirect effect from the social frailty level to functional status level through subjective cognitive function level was significant (β = -0.14, 95% CI -0.29, -0.09); the rates of change in subjective cognitive function mediated the relationship between those in social frailty and functional status (β = -0.35, 95% CI -0.46, -0.25)., Conclusions and Implications: This study found that there is an association between social frailty and functional status in Japanese older adults. Subjective cognitive function mediated this relationship. Hence, additional research is required to investigate additional potential factors linking social frailty and functional status in order to gain a better understanding of the underlying mechanisms., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Recent developments in the retinal hyperspectral imaging method have indicated its potential in addressing challenges posed by neurodegenerative disorders, such as Alzheimer's disease. This human clinical study is the first to assess reflectance spectra obtained from this imaging as a tool for diagnosing patients with Parkinson's disease (PD)., Methods: Retinal hyperspectral imaging was conducted on a total of 40 participants, including 20 patients with PD and 20 controls. Following preprocessing, retinal reflectance spectra were computed for the macular retina defined by four rectangular regions. Linear discriminant analysis classifiers underwent training to discern patients with PD from control participants. To assess the performance of the selected features, nested leave-one-out cross-validation was employed using machine learning. The indicated values include the area under the curve (AUC) and the corresponding 95% confidence interval (CI)., Results: Retinal reflectance spectra of PD patients exhibited variations in the spectral regions, particularly at shorter wavelengths (superonasal retina, wavelength < 490 nm; inferonasal retina, wavelength < 510 nm) when compared to those of controls. Retinal reflectance spectra yielded an AUC of 0.60 (95% CI: 0.43-0.78) and 0.60 (95% CI: 0.43-0.78) for the superonasal and inferonasal retina, respectively, distinguishing individuals with and without PD., Conclusion: Reflectance spectra obtained from retinal hyperspectral imaging tended to decrease at shorter wavelengths across a broad spectral range in PD patients. Further investigations building upon these preliminary findings are imperative to focus on the retinal spectral signatures associated with PD pathological hallmarks, including α-synuclein., Competing Interests: Declaration of competing interest The authors state that they have no conflicts of interest associated with this study. Outside the submitted work, Dr. Watanabe received lecture fees from Novartis Pharma, Viatris and Daiichi Sankyo; Dr. Matsuse received lecture fees from Daiichi Sankyo, Takeda Pharmaceuticals, Ono Pharmaceutical, Eisai, Otsuka Pharmaceutical, abbvie, Sumitomo Dainippon Pharma, Kyowa Kirin, EA Pharma, FP Pharmaceutical; Dr. Tanaka received lecture fees from Novartis Pharma and Takeda Pharmaceuticals; Dr. Isobe received lecture fees from Daiichi Sankyo, Takeda Pharmaceuticals, Ono Pharmaceutical, Eisai, Otsuka Pharmaceutical, Kyowa Kirin, EA Pharma, FP Pharmaceutical, Novartis, Mitsubishi Tanabe Pharma, and research supports from Otsuka Pharmaceutical, Sumitomo Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceuticals, Ono Pharmaceutical, Eisai, Kyowa Kirin, EA Pharma, Mitsubishi Tanabe Pharma, Novartis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Antiplatelet agents are effective for secondary prevention of ischemic stroke and can reduce the severity of first-ever ischemic stroke. However, it is uncertain if prophylactic antiplatelet therapy reduces the severity of recurrent ischemic stroke. The aim of this study was to determine the effect of preceding antiplatelet treatment on the severity of thrombotic stroke (TS) in patients with a prior history of stroke., Methods: From a prospective hospital registry of 1338 consecutive patients with acute ischemic stroke, we identified patients with a prior history of stroke who were admitted for cardioembolic stroke (CE); TS including large-artery atherosclerosis, small vessel occlusion, and branch atheromatous disease; or other cause or cryptogenic stroke (OCS). Cases in each subtype were categorized based on preceding medication: antiplatelet agents (AP) and none (N). Severity of stroke (National Institutes of Health Stroke Scale: NIHSS) on admission was compared between AP and N cases., Results: The total cohort of 252 patients included 83 with CE, 102 with TS, and 67 with OCS. After excluding those with prior anticoagulants, the median NIHSS on admission was lower in AP cases than in N cases (3 vs. 5, p = 0.002). In multivariate analysis, preceding AP treatment was independently associated with minor stroke (NIHSS ≤4) on admission in CE group (OR 8.48, 95% CI 1.71-62.9, p = 0.008) and TS group (OR 4.24, 95% CI 1.44-13.4, p = 0.009)., Conclusion: Preceding antiplatelet treatment in patients with a prior history of stroke may reduce the severity of subsequent thrombotic and cardiogenic stroke., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Although RNF213 p.R4810K, a genetic susceptibility variant for moyamoya disease (MMD), is associated with intracranial artery stenosis/occlusion (ICASO), the impact of this variant on ischemic stroke patients in non-young adults is unclear. We aimed to determine the characteristics of non-young adult stroke patients with RNF213 p.R4810K., Methods: We retrospectively identified acute ischemic stroke patients ≥50 years who were admitted to our hospital and underwent intracranial vascular imaging. We reviewed the patients with RNF213 p.R4810K and compared stroke characteristics and the frequency and location of ICASO between patients with and without the variant., Results: Among 341 patients, RNF213 p.R4810K was identified in 7 patients (2.1%). Five of the 7 patients with the variant (71%) had multiple ICASO without any finding of MMD and remaining 2 patients had no ICASO. The presumed etiologies of ICASO were atherosclerosis in 3 cases, vasculitis in 1, and undetermined vasculopathy in 1. ICASO in the anterior circulation was more common in patients with the variant than in those without (71% vs. 25%). The internal carotid artery, the M1 segment of the middle cerebral artery, the A1 segment of the anterior cerebral artery, and the P1 segment of the posterior cerebral artery, which were the most frequently affected arteries in MMD, were more often affected in the variant group., Conclusions: Non-young adult stroke patients with RNF213 p.R4810K are more likely to have ICASO in arterial segments commonly affected in MMD. The etiology of their ICASO exhibited diverse mechanisms, possibly depending on vascular risk and other environmental factors., (Copyright © 2023. Published by Elsevier B.V.)

A 38-year-old man who was delivered in a breech position presented with delayed development of secondary sexual characteristics and malaise. He was diagnosed with panhypopituitarism caused by interruption of the pituitary stalk due to perinatal complications. Brain magnetic resonance imaging findings for pituitary stalk interruption syndrome are well-documented; however, reports of the imaging findings of the bones and several organs related to the effects of panhypopituitarism are limited. In this patient with anterior pituitary dysfunction, imaging revealed diverse sequelae, including delayed skeletal maturation, osteopenia, genital atrophy, fatty liver, and adrenal atrophy. Radiologists may find it difficult to discern complex imaging findings unless they are informed of the clinical course of the patient. Therefore, radiologists should coordinate with clinicians to arrive at a diagnosis., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Sotos syndrome is a genetic disorder characterized by overgrowth in childhood, specific facial manifestations, advanced bone age, and mental retardation. The purpose of this article is to describe the nonsurgical orthodontic treatment of a 10-year-old boy with a skeletal mandibular protrusion, unilateral posterior crossbite, and Sotos syndrome. After maxillary lateral expansion, the skeletal Class III relationship with an anterior crossbite improved because of mandibular clockwise rotation, whereas the facemask had a marginal effect. After growth at 16 years, he had a skeletal Class I relationship, and thus, conventional orthodontic treatment with preadjusted edgewise appliances was initiated. After 41 months of multibracket treatment, acceptable occlusion with a functional Class I relationship was obtained. One year postretention, few changes in occlusion and facial features were observed. Our results demonstrate that considering the maxillofacial vertical growth during the peripubertal period associated with Sotos syndrome, more attention should be paid to the early orthopedic treatment with the facemask and/or chincap., (Copyright © 2022 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Shewanella algae (S. algae) is a rare bacterium that causes infectious diseases in humans. Herein, we present a case of an 84-year-old man with S. algae-induced bacteremia and performed a review of 12 cases identified via a literature search and this case. Literature review of previous reports in Japan have revealed that 69.2% of patients with S. algae-induced bacteremia had a history of contact with fresh fish. Appropriate interviews of patients, especially in the hot season, and the accurate identification of the causative bacterium, by using techniques such as MALDI-TOF-MS and genetic testing, are necessary if S. algae or other bacteria from the genus Shewanella are detected in blood-culture tests., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Podocyte damage is a major pathological lesion leading to focal segmental glomerulosclerosis (FSGS). Podocytes damaged by cellular stress undergo hypertrophy to compensate for podocytopenia. It is known that cyclin-dependent kinase inhibitors induced by p53 ensure podocytes hypertrophy; however, its precise mechanism remains to be further investigated. In this study, we found that ubiquitin specific protease 40 (USP40) is a novel regulator of p53. Although USP40 knockout mice established in the present study revealed no abnormal kidney phenotype, intermediate filament Nestin was upregulated in the glomeruli, and was bound to and colocalized with USP40. We also found that USP40 deubiquitinated histidine triad nucleotide-binding protein 1 (HINT1), an inducer of p53. Gene knockdown experiments of USP40 in cultured podocytes revealed the reduction of HINT1 and p53 protein expression. Finally, in glomerular podocytes of mouse FSGS, upregulation of HINT1 occurred in advance of the proteinuria, which was followed by upregulation of USP40, p53 and Nestin. In conclusion, USP40 bound to Nestin deubiquitinates HINT1, and in consequence upregulates p53. These results provide additional insight into the pathological mechanism of podocyte hypertrophy in FSGS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: A recent pandemic of SARS-CoV-2 infection has caused severe health problems and substantially restricted social and economic activities. RT-qPCR plays a vital role in the diagnosis of SARS-CoV-2 infection. The N protein-coding region is widely analyzed in RT-qPCR to diagnose SARS-CoV-2 infection in Japan. We recently encountered two cases of SARS-CoV-2-positive specimens showing atypical amplification curves in the RT-qPCR., Methods: We performed whole-genome sequencing of 63 samples (2 showing aberrant RT-qPCR curve and 61 samples infected with SARS-CoV-2 simultaneously in the same area) followed by Phylogenetic tree analysis., Results: We found that the viruses showing abnormal RT-qPCR curves were Delta-type variants of SARS-CoV-2 with a single nucleotide mutation in the probe-binding site. There were no other cases with the same mutation, indicating that the variant had not spread in the area. After searching the database, hundreds of variants were reported globally, and one in Japan contained the same mutation. Phylogenetic analysis showed that the variant was very close to other Delta variants endemic in Japan but quite far from the variants containing the same mutation reported from outside Japan, suggesting sporadic generation of mutant in some domestic areas., Conclusions: These findings propose two key points: i) mutations in the region used for SARS-CoV-2 RT-qPCR can cause abnormal amplification curves, and ii) various mutations can be generated sporadically and unpredictably; therefore, efficient and robust screening systems are needed to promptly monitor the emergence of de novo variants., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: The number of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains are increasing, further raising healthcare concerns worldwide. In this study, we isolated three CRKP strains from bile and blood samples of an elderly patient (90s) with acute cholangitis and characterised the features and antimicrobial resistance mechanism of CRKP isolates., Methods: Three CRKP isolates were characterised by Pulsed-field gel electrophoresis (PFGE), whole genome sequencing using the NovaSeq 6000, and antimicrobial susceptibility testing. Transcriptional levels of resistance-associated genes were measured by real-time RT-qPCR., Results: PFGE analysis revealed highly similar patterns for these isolates. Furthermore, they showed resistance to not only carbapenem but also tigecycline. Genomic analysis of the blood isolate identified the exogenous resistance genes bla CTX-M14 , tet(A), tet(D), opxAB, and qnrS1 but not any carbapenemase-encoding genes. In addition, nonsense mutations were found in both the outer membrane protein K36 (ompK36) and transcriptional regulator ramR, suggesting that this isolate developed multidrug resistance by acquiring both exogenous resistance genes and nonsense mutations. The extended-spectrum β-lactamase-producing carbapenem-susceptible K. pneumoniae isolate exhibited the same susceptibility pattern, except to β-lactams, as prior CRKP isolates., Conclusions: Antimicrobial susceptibility to carbapenem and tigecycline should be continuously monitored, because it might change from susceptible to resistant during another antimicrobial treatment, even if an isolate initially shows susceptibility, and the patient has not been exposed to these agents., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: HBV causes hepatocellular carcinoma (HCC). While it was recently shown that the ability of HBV X protein (HBx) to impair the Smc5/6 (structural maintenance of chromosome 5/6) complex is important for viral transcription, HBx is also a potent driver of HCC. However, the mechanism by which HBx expression induces hepatocarcinogenesis is unclear., Methods: Degradation of the Smc5/6 complex and accumulation of DNA damage were observed in both in vivo and in vitro HBV infection models. Rescue experiments were performed using nitazoxanide (NTZ), which inhibits degradation of the Smc5/6 complex by HBx., Results: HBx-triggered degradation of the Smc5/6 complex causes impaired homologous recombination (HR) repair of DNA double-strand breaks (DSBs), leading to cellular transformation. We found that DNA damage accumulated in the liver tissue of HBV-infected humanized chimeric mice, HBx-transgenic mice, and human tissues. HBx suppressed the HR repair of DSBs, including that induced by the CRISPR-Cas9 system, in an Smc5/6-dependent manner, which was rescued by restoring the Smc5/6 complex. NTZ restored HR repair in, and colony formation by, HBx-expressing cells., Conclusions: Degradation of the Smc5/6 complex by HBx increases viral transcription and promotes cellular transformation by impairing HR repair of DSBs., Lay Summary: The hepatitis B virus expresses a regulatory protein called HBV X protein (or HBx). This protein degrades the Smc5/6 complex in human hepatocytes, which is essential for viral replication. We found that this process also plays a key role in the accumulation of DNA damage, which contributes to HBx-mediated tumorigenesis., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Multiple myeloma (Plasma cell myeloma), a malignancy of the plasma cells, exhibits tumor expansion preferentially in the bone marrow and the development of bone-destructive lesions. Multiple myeloma is still an incurable disease with changes in the bone marrow microenvironment in favor of the survival and proliferation of multiple myeloma cells and bone destruction. In this review, we described the recent findings on the regulators involved in the development of myeloma bone diseases, and succinctly summarize currently available therapeutic options and the development of novel bone modifying agents for myeloma treatment., (© 2021 The Authors.)

Background and Overview: The authors successfully treat a case of hemifacial microsomia involving unilateral condylar hypoplasia using conventional orthodontic techniques followed by long-term retention., Case Description: A girl aged 10 years and 2 months received a diagnosis of hemifacial microsomia resulting from unilateral condylar hypoplasia. During a growth period, premature incisal contact was abolished. After her growth was complete, she received conventional orthodontic treatment with preadjusted edgewise appliances. After 27 months of multibracket treatment, acceptable occlusion with a class I canine and molar relationship was achieved. The occlusion remained stable throughout the 15-year retention period, although there was a slight facial change., Conclusions and Practical Implications: Early orthodontic management only can have some limitations but could be one of the treatment options for hemifacial microsomia., (Copyright © 2021 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1 . For wild-type WT1 , 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or -KTS]), and imbalance of the +KTS/-KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated., Methods: We conducted an in vitro minigene splicing assay for 6 reported causative variants and in vivo RNA sequencing to determine the +KTS/-KTS ratio using patients' samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype., Results: The in vitro assay revealed that although all mutant alleles produced -KTS transcripts only, the wild-type allele produced both +KTS and -KTS transcripts at a 1:1 ratio. In vivo RNA sequencing showed that patients' samples with all heterozygous variants produced similar ratios of +KTS to -KTS (1:3.2-1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period., Conclusion: Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Haemophilus influenzae with a reduced susceptibility to quinolones (quinolone low-susceptible H. influenzae) has recently emerged in Japan. In addition, the regional outbreak of the quinolone low-susceptible H. influenzae ST422 clone has been reported. In this study, we isolated this clone from an acute care hospital located in a geographically different area from the previous outbreak and characterised the nature of this clone., Methods: Eighty-nine H. influenzae isolated between 2017 and 2019 were tested. The antimicrobial susceptibility was determined by the broth dilution method. The genetic background was analysed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. Growth ability and β-lactamase acquisition were evaluated by growth curve analysis and conjugative transfer experiments, respectively., Results: Quinolone low-susceptible isolates accounted for 4.2% (1/24) in 2018 and 13.9% (5/36) in 2019. Most of the quinolone low-susceptible strains (83.3%) were classified as ST422 and had amino acid substitutions in quinolone resistance-determining regions in both GyrA and ParC. The patients' backgrounds were highly diverse. In addition, these isolates showed the same PFGE pattern as outbreak strains. The growth of ST422 clone was relatively faster than other clones. Furthermore, ST422 clone was able to acquire β-lactamase from a β-lactamase positive strain by horizontal transfer, becoming highly resistant to β-lactams., Conclusion: Our study indicated that the quinolone low-susceptible H. influenzae ST422 clone has been spreading in the community undetected. In addition, this clone has the potential to grow faster and become more resistant through exogenous gene transfer. Therefore, ST422 clone should be monitored attention throughout Japan., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The disc of the temporomandibular joint (TMJ) is located between the mandibular condyle and temporal bone, and has an important load-bearing and stress absorbing function. The TMJ disc presents viscoelastic characteristics that are largely dependent on its collagen fibre and proteoglycan composition and organization. The purpose of this study is to investigate the possible effects of region-specific dynamic viscoelastic properties on stress relaxation during prolonged clenching. Two finite element models were used to compare the stress distribution within the TMJ disc, namely, one with uniform disc material property and another one with region-specific disc material properties. Similar results were observed in both models with slight differences in the location of maximum stress. Larger stresses were observed in all cases for the model with uniform disc material property. Moreover, the higher values for the model with uniform disc material property appeared in the lateral region, while in the model with region-specific disc properties, these values moved to the lateral and central region. This investigation confirms that both models are sufficiently accurate to investigate stress distribution in the TMJ disc, and, particularly, the model with the region-specific disc material properties ensure better simulations of the TMJ disc behaviour., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The quality of life (QOL) and mental health of people who use drugs (PWUD) in the Philippines, especially those living in poor urban communities, are highly concerning due to the situations surrounding drug use and the ongoing hard-line antidrug policy. This study aimed to investigate the QOL and mental health status of PWUD, compare them with a comparison group with no history of drug use, and identify factors associated with QOL among Filipino PWUD., Methods: A cross-sectional study was conducted with recruitment from a community-based rehabilitation programme and poor urban communities in Muntinlupa in 2018. QOL was measured using the WHOQOL-BREF, while psychological distress and posttraumatic stress disorder (PTSD) were measured using the Kessler Psychological Distress Scale (K-6) and the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5), respectively. Multivariable linear regressions with each WHOQOL-BREF domain as a dependent factor were conducted to establish three predictions: age- and gender-adjusted QOL means, factors associated with QOL among PWUD, and interaction of lifetime drug use with each covariate., Results: In total, 272 PWUD and 402 comparison participants were recruited. Most PWUD were current drug users (53%), primarily of methamphetamine (70%). Among PWUD, the prevalence of moderate to severe psychological distress was 70%, and probable PTSD was 28%-both rates higher than those among the comparison group. All four QOL domain scores (physical, psychological, social, and environmental) of PWUD were lower than those of the comparison group. Multivariable regressions showed that psychological distress, current drug use, selling drugs, experiencing discrimination, and being never-married were associated with lower QOL. Higher individual income, household resources, social activity participation, and service use for drug use problems were associated with higher QOL among PWUD. Stratified and interaction analyses revealed that the QOL of PWUD was more sensitive to changes in individual income relative to the QOL of comparison group., Conclusion: A comprehensive intervention addressing psychological distress reduction, economic empowerment, and social inclusion-complementary to abstinence-oriented programmes-may improve the well-being of Filipino PWUD., Competing Interests: Declarations of Interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Overview: Patients with severe periodontitis often experience pathologic tooth migration (PTM), which impairs esthetics and leads to occlusal disharmony (for example, premature contacts and traumatic occlusion) that can further exacerbate periodontitis. The authors describe a patient who exhibited severe periodontitis with PTM-related bimaxillary protrusion. This report includes 3-year clinical outcomes after periodontal regenerative therapy, implant-anchored orthodontic therapy, and implant prosthodontics intended to achieve both functional and esthetic improvements., Case Description: A 63-year-old woman sought treatment with the chief complaint of maxillary anterior tooth mobility. Clinical examination revealed excessive tooth mobility, deep periodontal pockets, and infrabony defects in all teeth. All teeth exhibited PTM; the mandibular anterior teeth exhibited marked protrusion caused by the progression of periodontitis. After initial periodontal therapy, periodontal regenerative therapy was performed in all molar regions. At 6 and 9 months postoperatively, comprehensive orthodontic treatment was initiated for the mandible and maxilla, respectively, using orthodontic anchorage devices to achieve acceptable functional occlusion. After orthodontic treatment, staged guided bone regeneration was performed and dental implants were placed in the severely resorbed maxillary anterior ridge. This comprehensive treatment yielded favorable periodontal conditions, stable occlusion, and good esthetic outcomes., Conclusions and Practical Implications: Favorable esthetics, stable occlusion, and highly cleansable periodontal tissues were achieved with well-planned interdisciplinary and comprehensive treatment, although the patient had severe periodontitis and PTM-related bimaxillary protrusion., (Copyright © 2021 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Introduction: There is some evidence that Bordetella pertussis (B. pertussis) can co-infect with viral respiratory infections in young infants., Methods: B. pertussis infection was studied by culture, polymerase chain reaction (PCR), and loop-mediated isothermal amplification (LAMP) from nasopharyngeal swabs (NPSs) in 49 infants < 12 months of age, who were admitted for lower respiratory tract infections during the winter season. Seven other possible viral pathogens were documented by antigen detection or PCR in NPSs. The clinical feature of infants with mixed infection of B. pertussis and respiratory viruses were examined., Results: Overall, B. pertussis infection was found in 10 (20.4%) cases, nine were less than 6 months of age and seven were unvaccinated. Viral etiology was found in 41 (84%) cases and pertussis-viral co-infection was present in eight patients, five of whom had mixed infection with respiratory syncytial virus. Only the presence of staccato coughing, cyanosis, and lymphocytosis were significantly different in B. pertussis-positive cases compared with B. pertussis-negative cases. Of the 10 pertussis cases, only the culture-positive cases showed the typical symptoms and laboratory findings of pertussis in addition to virus-associated respiratory symptoms with severe hospital course, whereas cases identified as DNA-positive lacked the characteristics of pertussis and their clinical severities were the same as B. pertussis-negative cases., Conclusion: In the absence of typical paroxysmal cough and lymphocytosis, we should carefully consider diagnosis of pertussis in young children hospitalized for presumed viral respiratory illness according to local epidemiological surveillance., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Open bite is considered one of the most complicated malocclusions in orthodontic treatment. In this study, the authors successfully treated total open bite involved in hypercementosis using orthodontic miniscrews., Case Description: A woman aged 25 years 8 months had total open bite. Her occlusal contact at the maximum intercuspation was present at the right second molars. A panoramic radiograph showed diffuse hypercementosis. The titanium miniscrews were interradicullay implanted between the first and second molars, and intrusion force was applied for 14 months. After active treatment, the patient's maxillary first molars showed about 1.6-millimeters of intrusion, resulting in counterclockwise mandibular rotation. Her acceptable occlusion was maintained after 1.0-year retention., Practical Implications: Miniscrews might be useful tool to improve malocclusion involved in diffuse hypercementosis though they are considered to be difficult to move and brought on ankylosis., (Copyright © 2021 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Parafunctional habits, such as bruxism and prolonged clenching, have been associated with dysfunctional hyperactivity of the masticatory muscles, including the lateral pterygoid muscle. The resultant loading to the temporomandibular joint (TMJ) is subject to the degradation of bone, cartilage and disc in the TMJ. In this study, we examined the effect of clenching direction on the stress distribution in the TMJ. In this line, we hypothesised that asymmetrical clenching involved in parafunction might result in increased stresses on the TMJ disc as well as on the condylar and temporal articular surfaces. The distribution of stress for various directional loadings was analysed using a three-dimensional finite element model of the TMJ, with viscoelastic properties for the disc. The numerical results revealed that load direction influenced the amount and distribution of stresses on the disc surfaces. In particular, the lateral region of the disc suffered higher stress values. Moreover, the results showed a significant stress relaxation in the disc that revealed its capacity for stress energy dissipation. From the present study, it can be established that during prolonged clenching, the higher stresses are concentrated in the lateral region, which could imply that TMJ disorders related to damage or wear in the disc and the condylar cartilage, overall, occur when lateral dysfunctional displacements are present., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background & Aims: HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study., Methods: HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation., Results: Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p <0.05)., Conclusions: A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation., Clinical Trial Number: UMIN000001299., Lay Summary: Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation., Competing Interests: Conflicts of interest Shigeru Kusumoto: Research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., and honoraria from Chugai Pharmaceutical Co., Ltd., Zennyaku Kogyo Co. Ltd., Bristol-Myers Squibb. Yasuhito Tanaka: Research funding from Fujifilim Corp., Gilead Sciences Inc., Bristol-Meyers Squibb, Chugai Pharmaceutical Co., Ltd., Fujifilim Corp., Janssen Pharmaceutical K.K, Glaxosmithkline pharmaceuticals ltd, Stanford Junior University and and Honoraria from Fujirebio Inc., Gilead Sciences Inc. Bristol-Meyers Squibb, Sysmex Corp. Ritsuro Suzuki: Honoraria from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Bristol-Meyers Squib, Meiji Seika, MSD, Takeda, Celgene, Eisai, Ono Pharmaceuticals, Janssen, AbbVie, Novartis, Shionogi, Ohtsuka, Sawai, Sumitomo Dainippon, Alexion Pharma, Sanofi, Gilead Sciences, Jazz Pharma. Takashi Watanabe: Funding resources from TakaraBio and United Immunity, Co., Ltd., to support Department of Immuno-Gene Therapy in Mie University Graduate School of Medicine, to which TW belongs, and honoraria from Bristol-Meyers Squibb, AstraZeneca Pharmaceutical, and Chugai Pharmaceutical Co., Ltd. Rika Sakai: Research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Ono Pharmaceuticals, Yakult, Taiho Pharma, and Eisai and honoraria from Takeda, Bayer, Bristol-Meyer-Squibb, Sumitomo Dainippon, Celgene, Mundipharma, Eisai, and Kyowa Kirin Co., Ltd. Kuniaki Itoh: Consultant or Advisory Role on Zennyaku Kogyo Co. Ltd. Kisato Nosaka: Honoraria from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Bristol-Myers Squibb, Celgene K.K. Masashi Sawa: Honoraria from Chugai, Pfizer, Astellas, Nippon-Shinyaku, Ono, MSD, Bristol-Myers Squibb, Kyowa-Hakko Kirin, Asahi-Kasei, Novartis, Eisai, Otsuka, Sumitomo Dainippon, Sanofi, Takeda, Celgene, Mochida, Shire, Mundipharma. Rumiko Okamoto: Honoraria from Kissei, Celgene, Chugai. Toshiki Uchida: Honoraria from Pfizer, Chugai Pharmaceutical, Takeda Pharmaceutical, Janssen Pharmaceutical, Eisai, Celgene, Mundipfarma, Bristol-Myers Squibb, Ono Pharmaceutical, Novartis Pharma, Otsuka Pharmaceutical, Nippon Shinyaku, Kyowa Kirin. Masataka Okamoto: Research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Taiho Pharma, Takeda Pharmaceutical Co. Ltd., Ono Pharmaceutical Co., Ltd. Yasushi Onishi: Research funding from Takeda, Bristol-Myers Squibb, MSD, and honoraria from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Bristol-Myers Squibb, Pfizer, Astellas, Novartis, Celgene, Sumitomo Dainippon, Ono, Nippon Shinyaku, Janssen. Otsuka, MSD. Hiroyuki Takahashi: Consultant or Advisory role on Celgene, Takeda, Chugai Pharmaceutical Co., Ltd., honoraria from Kyowa Kirin Co., Ltd., Bristol-Meyers Squibb, Novartis, Ono, Janssen. Akihiro Tomita: Research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Taiho Pharma, and honoraria from Chugai Pharmaceutical Co., Ltd. Yoshiko Atsuta: Honoraria from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Mochida, Meiji Seika, Bristol-Myers Squibb, Yakult Honsha, Janssen. Dai Maruyama: Research funding from Chugai Pharmaceutical Co., Ltd., Zennyaku Kogyo Co. Ltd., Ono Pharmaceutical, Celgene, Takeda Pharmaceutical, Janssen Pharmaceutical, Bristol-Myers Squibb, Merck, Amgen Astellas BioPharma, Astellas Pharma, Sanofi, Novartis Pharma, Otsuka Pharmaceutical and honoraria from Chugai Pharmaceutical Co., Ltd., Zennyaku Kogyo Co. Ltd., Ono Pharmaceutical, Celgene, Takeda Pharmaceutical, Janssen Pharmaceutical, Eisai, Kyowa Hakko Kirin, Bristol-Myers Squibb, SYNMOSA BIOPHARMA, NIPPON SHINYAKU. Eiji Tanaka: Honoraria from Sysmex Corporation. Tomohiro Kinoshita: Research funding from Takeda, Chugai, Ono, MSD, Eisai, Gilead, Zenyaku, Soleisia, and honoraria from Takeda, Chugai, Ono. Michinori Ogura: Consultant or Advisory Role on Celgene, Celltrion, Teva-Takeda, MeijiSeika Pharma, Mundi Pharma, Verastem, SymBio, Denovo Biopharma, Yakult, Eisai, and honoraria from Celgene, Takeda, MeijiSeika Pharma, Chugai. Ryuzo Ueda: Consultant or Advisory Role on Terumo Co., Ltd., and research funding from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Rikaken Co., Ltd., Medical & Biological Laboratories Co., Ltd. Masashi Mizokami: Honoraria from Gilead Sciences, Sysmex Corporation. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen., Patients and Methods: Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m 2 /day), doxorubicin (10 mg/m 2 /day), and vincristine (0.4 mg/m 2 /day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m 2 /day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert's formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6., Results: In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation., Conclusion: The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

MSX1 is a causative gene for oligodontia in humans. Although conventional Msx1-deficient mice die neonatally, a mutant mouse lacking the C-terminus MH6 domain of MSX1 (Msx1 ΔMH6/ΔMH6 ) showed two different phenotypes; newborn homozygotes with cleft palates died neonatally, whereas those with thin palates remained alive and had craniofacial dysplasia and growth retardation compared with wild-type mice, with most mice dying by the age of 4-5 weeks. In a previously reported case of human oligodontia caused by a heterozygous defect of the Msx1 MH6 domain, a small foramen was observed on the occipital bone. The aim of this study was to test the hypothesis that the Msx1 MH6 domain is involved in bone formation in vivo. In Msx1 ΔMH6/ΔMH6 mice, cranial suture fusion was delayed at embryonic day 18.5, and the anteroposterior cranial diameter was smaller and long bone length was decreased at 3 weeks of age. The femoral epiphysis showed no change in the trabecular number, but decreased bone mass, bone density, and trabecular width in Msx1 ΔMH6/ΔMH6 mice. In addition, cancellous bone mass was reduced and the cartilage layer in the growth plate was thinner in Msx1 ΔMH6/ΔMH6 mice. The mRNA expression levels of major osteoblast and chondrocyte differentiation marker genes were decreased in Msx1 ΔMH6/ΔMH6 mice compared with wild-type mice. These findings suggest that the C-terminal region including the MH6 domain of MSX1 plays important roles not only in tooth development and palatal fusion, but also in postnatal bone formation., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Haemophilus influenzae strains with reduced susceptibilities to antimicrobial agents have emerged in Japan. Here, we aimed to investigate H. influenzae non-susceptibility to β-lactams and non-β-lactams., Methods: A total of 260 H. influenzae isolates from patients in 2013-2016 were analysed. Antimicrobial susceptibilities were assessed by determining the minimum inhibitory concentration. Additionally, isolates with reduced susceptibility were analysed by both genetic and statistical methods., Results: β-Lactamase-non-producing ampicillin-resistant H. influenzae (BLNAR) strains increased significantly and accounted for more than 50% of all isolates from 2014. Additionally, the proportion of quinolone-low-susceptibility isolates increased significantly (P<0.05). Among these, three quinolone-non-susceptible isolates showed minimum inhibitory concentrations higher than the susceptibility breakpoint of levofloxacin. Moreover, one of the three isolates showing multidrug resistance was resistant to macrolides, β-lactams, and quinolones. Low susceptibilities to non-β-lactams were significantly associated with BLNAR., Conclusions: The present study indicates that BLNAR strains are increasing and tend to show multidrug resistance. Additionally, multidrug-resistant H. influenzae (MDRHI) has emerged. To prevent the further spread of MDRHI, the proportions of BLNAR strains should be evaluated., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Social relationships may help in maintaining functional status among older adults. This study examined the types of social relationships that were related to functional status among Japanese community-dwelling older adults., Study Design: This is a prospective cohort study., Methods: We used baseline data from 2008 and conducted follow-up surveys six years later. Participants included individuals older than 65 years who lived in a suburban community in Japan. The Index of Social Interaction measure was used to assess multiple elements of social relationships. Two functional status outcomes were set: (1) functional decline and (2) functional decline and mortality. A multiple logistic regression model was used to examine the association between social relationships and functional decline six years later., Results: After controlling for age, sex, family structure and disease status in 2008, poor social curiosity (odds ratio [OR] = 1.31, 95% confidence interval [CI]: 1.02-1.69) and interaction (OR = 2.57, 95% CI: 1.20-5.51) were found to be associated with functional decline. Furthermore, social curiosity (OR = 1.39, 95% CI: 1.14-1.69) and interaction (OR = 2.84, 95% CI: 1.44-5.59) were also associated with the composite outcome., Conclusions: Social curiosity and interacting with others were significantly associated with functional status. Promotion of social interaction may be essential for preventing future need for care., (Copyright © 2019 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Introduction: Because mechanical stimulation of the periodontal ligament by low-intensity pulsed ultrasound (LIPUS) has been shown to increase the speed of bone remodeling, this study aimed to examine the effects of LIPUS stimulation on the rate of tooth movement and bone remodeling during lateral tooth movement., Methods: Twelve-week-old Wistar rats were divided into 2 groups. The LIPUS group received experimental tooth movement with LIPUS stimulation, and the tooth movement (TM) group were provided experimental tooth movement without LIPUS. For each group, the upper right first molars were moved buccally with fixed appliances. LIPUS exposure was placed in the region corresponding to the right maxillary first molar. Three days after tooth movement, tartrate-resistant acid phosphatase was examined. Fourteen days after tooth movement, the intermolar width, bone mineral content, and bone volume fraction were analyzed by micro-computed tomography, and newly formed bone was measured histomorphometrically., Results: The number of TRAP-positive cells in the compressed region was higher in the LIPUS group. The intermolar width was significantly higher in the LIPUS group than in the TM group. The alveolar bone around the maxillary first molar showed no differences in bone mineral content and bone volume fraction between the LIPUS and TM groups. The LIPUS group exhibited a more significant amount of newly formed alveolar bone than the TM group., Conclusions: The present study provides evidence of the beneficial effects of LIPUS on the lateral tooth movement., (Copyright © 2019 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Rheumatoid arthritis (RA) mainly affects various joints of the body, including the temporomandibular joint (TMJ), and it involves an infiltration of autoantibodies and inflammatory leukocytes into articular tissues and the synovium. Initially, the synovial lining tissue becomes engaged with several kinds of infiltrating cells, including osteoclasts, macrophages, lymphocytes, and plasma cells. Eventually, bone degradation occurs. In order to elucidate the best therapy for RA, a comprehensive study of RA pathogenesis needs to be completed. In this article, we discuss a Fas-deficient condition which develops into RA, with an emphasis on the role of sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling which induces the migration of osteoclast precursor cells. We describe that Fas/S1P 1 signaling via NF-κB activation in osteoclasts is a key factor in TMJ-RA severity and we discuss a strategy for blocking nuclear translocation of the p50 NF-κB subunit as a potential therapy for attenuating osteoclastogenesis.

Background and Overview: Previous studies have suggested that occlusal discrepancy is a risk factor contributing to periodontal disease. Occlusal discrepancy could increase the risk of developing infrabony defects. The authors present a case of a patient with severe periodontitis who exhibited many infrabony defects in the molar region due to malocclusion-induced trauma. They report the 7-year treatment outcomes of the patient after periodontal regenerative and comprehensive orthodontic therapies for functional recovery with implant prosthodontics., Case Description: A 56-year-old woman sought treatment with the chief symptom of masticatory disturbance. In the molar region, excessive tooth mobility, deep periodontal pockets, and infrabony defects were observed. She had excessive overjet, resulting in collapse of anterior guidance. Malocclusion was considered to be an exacerbating factor of the infrabony defects. After initial periodontal therapy, the authors performed periodontal regenerative therapy in the mandibular molar regions. The authors carefully placed implants in a position in the maxillary molar region that would ensure an appropriate anterior dental relationship after orthodontic treatment. Comprehensive orthodontic treatment was subsequently performed, using implants as anchoring units. Definitive surgery was then performed on the mandibular molars before placing the final prosthesis. Favorable periodontal condition and stable occlusion have been maintained for the 7-year posttreatment period., Conclusions and Practical Implications: Comprehensive and interdisciplinary treatment enables stable occlusion and establishment of periodontal and peri-implant tissues with high cleansability, even in patients with severe periodontitis and malocclusion. In this case, a favorable long-term treatment outcome can be expected., (Copyright © 2019 American Dental Association. Published by Elsevier Inc. All rights reserved.)

In paediatric patients, β-lactams and macrolides are widely used to treat acute otitis media and sinusitis, which are often caused by either Streptococcus pneumoniae or Haemophilus influenzae. However, resistant isolates have emerged and are becoming more prevalent. H. influenzae generally acquires antimicrobial resistance by mutation or by expression of β-lactamase. In this study, we isolated H. influenzae from a paediatric patient diagnosed with acute sinusitis. This strain harboured multiple exogenous resistance genes: bla TEM-1 , mef(A) and tet(M). DNA sequencing suggested that both mef(A) and tet(M) had been transferred from S. pneumoniae or another Streptococcus. This typical outpatient had not been exposed to excessive levels of antibiotics and had no underlying diseases, strongly suggesting that this type of resistant isolate could become more prevalent., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The demand for orthognathic surgery has increased worldwide. Women with jaw deformity tend to have a worse quality of life than men owing to the deformity's negative effects on body image, low self-esteem, lack of self-confidence, and dissatisfaction with life. Therefore, they wish for more reliable treatment options., Case Description: A woman aged 25 years and 9 months sought treatment for a convex profile and excessive gingival display caused by a skeletal Class II jaw-base relationship. Gingival exposure was up to 6.5 millimeters at full smile. She chose orthognathic surgery, and the authors performed a 2-piece segmental Le Fort I osteotomy and bilateral sagittal split ramus osteotomy. After active orthodontic treatment, the protrusive profile was improved, and an acceptable occlusion and an attractive smile were achieved., Practical Implications: It is hoped that 2-piece segmental Le Fort I osteotomy becomes a common treatment option for patients with protrusive profiles and excessive gingival displays., (Copyright © 2019 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Background & Aim: Hypertension as a risk factor for cardiovascular disease has growing prevalence. An increase in body weight is typically followed by an increase in blood pressure. This study aimed to investigate the association of general and central obesity with hypertension in Indonesian women using WHO and Indonesian classification systems., Methods: Cross-sectional study of Indonesian women aged 18 years or and more (313,714 participants), using national level Indonesia National Basic Health Research (2013)., Results: The prevalence of hypertension in Indonesian women in this study was 32.8%. Based on logistic regression analysis, hypertension was significantly associated with residential area, educational attainment, self-reported smoking status, cardiovascular disease, chronic kidney disease, diabetes mellitus, body mass index and waist circumference. Furthermore, the odds of having hypertension for general and central obesity according to WHO classification were adjusted odds ration (aOR) 2.61, 95% CI 2.52-2.70 and aOR 1.50, 95% CI 1.46-1.53. By Indonesian classification were aOR 2.21, 95% CI 2.16-2.26 and aOR 1.48, 95% CI 1.45-1.51., Conclusion: By using International WHO and standard Indonesia classification systems, general and central obesity were associated with hypertension in Indonesia women. Thus, not only general obesity but also central obesity should be used to assess obesity in Indonesian women., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

A 73-year-old woman was admitted with consciousness disturbance following a fever. Abdominal computed tomography revealed a large liver abscess with which the presence of Desulfovibrio desulfuricans and Escherichia coli was confirmed by thorough blood and abscess content culture. Empiric meropenem treatment was switched to cefoperazone/sulbactam, followed by ampicillin/sulbactam based on susceptibility testing. Desulfovibrio desulfuricans is a common bacterium that rarely causes liver abscess and may be overlooked during co-infection due to overgrowth of the accompanying bacteria. Clinicians should bear Desulfovibrio desulfuricans in mind and select the appropriate antibiotics according to susceptibility testing when anaerobic bacteria are detected in a liver abscess., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Biliary atresia (BA) is the most common indication for liver transplantation (LT) in pediatric population. This study analyzed the comprehensive factors that might influence the outcomes of patients with BA who undergo living donor LT by evaluating the largest cohort with the longest follow-up in the world. Between November 1989 and December 2015, 2,085 BA patients underwent LDLT in Japan. There were 763 male and 1,322 female recipients with a mean age of 5.9 years and body weight of 18.6 kg. The 1-, 5-, 10-, 15-, and 20-year graft survival rates for the BA patients undergoing LDLT were 90.5%, 90.4%, 84.6%, 82.0%, and 79.9%, respectively. The donor body mass index, ABO incompatibility, graft type, recipient age, center experience, and transplant era were found to be significant predictors of the overall graft survival. Adolescent age (12 to <18 years) was associated with a significantly worse long-term graft survival rate than younger or older ages. We conclude that LDLT for BA is a safe and effective treatment modality that does not compromise living donors. The optimum timing for LT is crucial for a successful outcome, and early referral to transplantation center can improve the short-term outcomes of LT for BA. Further investigation of the major cause of death in liver transplanted recipients with BA in the long-term is essential, especially among adolescents., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Perforin-2 is constitutively expressed in macrophages that are required for bacterial control. In this study, we found that perforin-2 is expressed in human macrophages with two isoforms: full-length perforin-2a and a splice variant, perforin-2b. Two isoforms show different subcellular distributions. Perforin-2a was predominantly localized to the membrane of endosome-like vesicles by a C-terminal transmembrane domain. In contrast, the short isoform perforin-2b lacking the transmembrane domain failed to localize to the membrane of vesicles. Furthermore, we determined that the pro-inflammatory stimuli LPS and TNF-α induced perforin-2a expression via the NF-κB pathway and triggered perforin-2a vesicles fusion with lysosomes. On the other hand, we detected the secretion of perforin-2b in response to LPS stimulation. Taken together, our data provide the evidence that membrane-bound and secretory isoforms of perforin-2 are present in human macrophages and may play important roles in immune defense., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Enhanced turnover of subchondral trabecular bone is a hallmark of rheumatoid arthritis (RA) and it results from an imbalance between bone resorption and bone formation activities. To investigate the formation and activation of osteoclasts which mediate bone resorption, a Fas-deficient MRL/lpr mouse model which spontaneously develops autoimmune arthritis and exhibits decreased bone mass was studied. Various assays were performed on subchondral trabecular bone of the temporomandibular joint (TMJ) from MRL/lpr mice and MRL+/+ mice. Initially, greater osteoclast production was observed in vitro from bone marrow macrophages obtained from MRL/lpr mice due to enhanced phosphorylation of NF-κB, as well as Akt and MAPK, to receptor activator of nuclear factor-κB ligand (RANKL). Expression of sphingosine 1-phosphate receptor 1 (S1P 1 ) was also significantly upregulated in the condylar cartilage. S1P 1 was found to be required for S1P-induced migration of osteoclast precursor cells and downstream signaling via Rac1. When SN50, a synthetic NF-κB-inhibitory peptide, was applied to the MRL/lpr mice, subchondral trabecular bone loss was reduced and both production of osteoclastogenesis markers and sphingosine kinase (Sphk) 1/S1P 1 signaling were reduced. Thus, the present results suggest that Fas/S1P 1 signaling via activation of NF-κB in osteoclast precursor cells is a key factor in the pathogenesis of RA in the TMJ., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The correct characterisation of the articular disc of the temporomandibular joint (TMJ) is key to study the masticatory biomechanics. For the interval from extraction until testing, freezing is the most used preservation technique for biological tissues, but its influence on their behaviour is still unclear. An important error can be committed in the characterisation of such tissues if freezing has any effect on their mechanical properties. Thus, the aim of this study was to determine whether the freezing storage time causes any change in the mechanical properties of the TMJ discs. To check that, the specimens were stored in a -20°C freezer during different time intervals: 1 day, 1 week, 1 month and 3 months. Fresh specimens, tested right after extraction, were used as the control group. Compressive stress relaxation tests were carried out on the specimens and a quasi-linear viscoelastic (QLV) model was used to fit the experimental curves. A statistical analysis detected significant differences among the groups. Post-hoc tests determined that freezing the specimens more than 30 days may lead to changes in the viscoelastic properties of the tissue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We successfully treated a patient with achondroplasia with conventional orthodontic techniques. It was followed by long-term retention. The patient, a 12-year-old boy, had chief complaints of occlusal disturbance and mandibular protrusion. He had been diagnosed with achondroplasia and had growth hormone treatment in his early teenage years. His facial profile was concave with a bulging forehead and a retrognathic maxilla. It was characterized by a skeletal Class III jaw-base relationship with a retropositioned maxilla. At the age of 12 years 9 months, maxillary protraction was initiated with a reverse headgear; for 2 years 6 months, the maxillomandibular growth was controlled. After the growth spurt, at the age of 15 years 6 months, leveling and alignment of both dental arches were started with preadjusted edgewise appliances. After 83 months of multibracket treatment, an acceptable occlusion with a Class I molar relationship and an adequate interincisal relationship was achieved, despite the simultaneous marked vertical growth of the mandible. The resultant occlusion was stable during a 6-year retention period, although considerable forward-downward mandibular growth was observed. Conclusively, our results indicated the necessity of long-term observation in this patient with achondroplasia, especially because of the persistent mandibular growth., (Copyright © 2017 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

We successfully treated a Class II Division 2 patient with maxillary group distalization using interradicular miniscrews. A woman, aged 28 years 11 months, had a convex profile and an excessive overjet caused by a skeletal Class II jaw-base relationship. After leveling and alignment, titanium miniscrews were obliquely implanted between the maxillary second premolar and first molar. To distalize the maxillary dentition, nickel-titanium closing coil springs with a 2-N load were placed between the screws and the hooks on the archwire. After 28 months of active orthodontic treatment, a proper facial profile and an acceptable occlusion were achieved with a 4-mm distalization of the maxillary dentition. The resultant occlusion was stable throughout a 5-year retention period. Interradicular miniscrews were useful to distalize the maxillary dentition for correcting a Class II malocclusion. This new strategy, group distalization with miniscrews, can make the treatment simpler with greater predictability., (Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

We successfully treated a 32-year-old woman who had facial asymmetry and unilateral mandibular condylar osteochondroma using ipsilateral mandibular condylectomy and contralateral ramus osteotomy. Mirror image analysis with a noncontact 3-dimensional image scanner showed that the soft tissue on the deviated side was protruded more than 5.50 mm compared with the nondeviated side. The patient was diagnosed as having facial asymmetry with a skeletal Class III jaw-base relationship caused by unilateral mandibular condylar osteochondroma. After 18 months of preoperative orthodontic treatment, an ipsilateral condylectomy and a contralateral sagittal split ramus osteotomy were performed. As the result of postoperative orthodontic treatment for 20 months, an ideal occlusion with a Class I molar relationship and an adequate interincisal relationship was achieved. Facial asymmetry and mandibular protrusion were dramatically improved, and the total differences between the deviated and nondeviated sides were decreased to less than 1.11 mm. The acceptable occlusion and the symmetric face were maintained throughout the 1-year retention period. Our results indicated stability after condylectomy without condylar reconstruction in a patient with unilateral condylar osteochondroma., (Copyright © 2016 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

In this study, the dynamic and static compressive properties of the whole porcine temporomandibular joint (TMJ) disc were investigated. The aim of the study was to develop a new simple method for the evaluation of joint viscoelasticity, enabling examination of the load-bearing capacity and joint flexibility of the entire disc. For the experiments, a novel testing fixture that reproduces the condylar and fossa surfaces of the TMJ was developed to replicate TMJ disc geometry. Ten porcine discs were used in the experiments. Each disc was dissected from the TMJ and sinusoidal compressive strain was applied to obtain the storage and loss moduli. Static strain control tests were carried out to obtain the relaxation modulus. The result of static and dynamic tests indicated that the whole disc presented viscoelastic behavior under compression. Storage and loss moduli increased with frequency and the relaxation modulus decreased over time. The loss tangent showed less frequency dependence, with values ranging from 0.2 to 0.3, suggesting that the viscous properties of the disc cannot be neglected. These results provide a better understanding of whole disc mechanical compression behavior under realistic TMJ working conditions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)